advances in lung transplantation “the best preservation solution for the worst graft”

EACTS 16th Annual MeetingMonte Carlo

Advances in Lung Transplantation

“The best preservation solution for the worst graft”

University Hospital Gasthuisberg, Leuven, Belgium

Dirk Van Raemdonck, MD, PhD,

FETCS

EACTS Postgraduate Courses

Session 3: General Thoracic Surgery

Sunday, 22 September 2002

Monte Carlo, Monaco


www.dirkvanraemdonck.be

This presentation is available online via


Overview

• ischemia - reperfusion injury

• lung donors

• preservation techniques

• preservation solutions

• reperfusion techniques

• conclusions



• lung donors




• conclusions


Definition

• post-transplant allograft dysfunction

• resulting from damage during

ischemia and reperfusion

• = pulmonary reimplantation response

I-R injury (1)


Incidence

• unpredictable

• 57% - 97% perihilar edema(Khan S. Chest 1999:116:187-94)(Anderson D. Radiology 1995:195:275-81)

• 10 - 20 % clinically significant(Zenati M. Transplantation 1990;50:165-67)

• 2 - 5% mortality(Hosenpud J. J Heart Lung Transplant 1996;15:655-74)(Meyers B. Ann Surg 1999;230:362-71)

I-R injury (2)


Clinical Manifestation

• poor oxygenation (low PaO2/FiO2 - high A-a DO2)

• low pulmonary compliance (Cdyn)

• interstitial / alveolar edema (fluid loss)

• pulmonary infiltrates (injury score on CXR)

• increased vascular resistance (PVR)

• intrapulmonary shunt (QS/QT)

• acute alveolar injury (DAD)

I-R injury (3)


Mechanisms

• complex (myriad cellular and molecular events)

• endothelial cell dysfunction(increased microvascular permeability)

• alveolar type II cell dysfunction

(pulmonary surfactant alterations)

(Novick RJ. Ann Thorac Surg 1996;62:302-14)

I-R injury (4)


Differential Diagnosis

• hyperacute rejection(Frost AE. Chest 1996;110:559-62)

• early infection

(Paradis IL. J Heart Lung Transplant 1992;11:S232-6)

• venous anastomotic obstruction(Leibowitz D. J Heart Lung Transplant 1994;13:S39)

• cardiogenic edema (left ventricular failure)

I-R injury (5)


Treatment • increased ventilation (FiO2 - PEEP) • negative fluid balance (diuretics)

• pulmonary vasodilation (PG - inhaled NO)(Aoe M. Ann Thorac Surg 1994;58:655-61)(Adatia I. Ann Thorac Surg 1994;57:1311-8)

• surfactant replacement (nebulized synthetic)(Struber M. Intensive Care Med 1999;25:862-4)

• extracorporeal oxygenation (ECMO)(Meyers B. J Thorac Cardiovasc Surg 2000;120:20-8)

• urgent retransplantation(Novick RJ. Ann Thorac Surg 1998;65:227-34)

I-R injury (6)


Impact

• increased morbidity & mortality

• prolonged ventilation

• prolonged ICU & hospital stay

• increased costs

(King RC. Ann Thorac Surg 2000;69:1681-5)

I-R injury (7)


Identified Risk Factors

I-R injury (8)

• donor-related- quality donor lung (age, cause of death, ventilation)

(Sundaresan S. J Thorac Cardiovasc Surg 1995;109:1075-80)

• preservation-related- preservation solution?- ischemic time?

• recipient-related- pulmonary hypertension

(Bando K. Ann Thorac Surg 1994;58:1336-42)- cardio-pulmonary bypass

(Francalancia N. J Heart Lung Transplant 1994;13:498-57)


I-R injury (9)

Early outcome

• ischemic time (0 – 40 points)

• recipient age (0 – 36 points)

• PaO2/FiO2 (0 – 80 points)

• hemodynamic failure (0 – 18 points)

Ischemia/Reperfusion Injury Severity Score

IRISS

(Thabut G et al. Chest 2002;121:1876-1882)


IRISS and mortality in ICU

I-R injury (10)

(Thabut G et al. Chest 2002;121:1876-1882)


I-R injury (11)Late outcome

Independent

Predictive Factor

For

BOS

(Fiser SM et al. Ann Thorac Surg 2002;73:1041-1048)



• lung donors




• conclusions

EACTS 16th Annual MeetingMonte CarloFinal Assessment

• bronchoscopy (endotracheal aspiration)

• imaging (recent chest x-ray)

• macroscopy (inspection - palpation)

(Sundaresan S et al. Ann Thorac Surg 1993;56:1409-1413)

• gas exchange (pulmonary vein gas analysis)

(Aziz TM et al. Ann Thorac Surg 2002;73:1599-1605)

Lung Donors (1)


Lung Donor Score

Lung Donors (2)

• donor age

• smoking history

• PaO2/FiO2

• x-ray findings

• bronchoscopic findings

Task Force in Pulmonary Committee of ISHLT(Waddell TK)


Lung Donors (3)

(Pierre AF et al. J Thorac Cardiovasc Surg 2002;123:421-427)

Recipient Outcome



• lung donors




• conclusions


Techniques (1)

Graft Cooling

• topical (NHBD)

• donor core cooling on CPB

• single pulmonary artery flush

(Hopkinson DN et al. J Heart Lung Transplant 1998;17:525-531)

EACTS 16th Annual MeetingMonte CarloControversie

s • flushing conditions (T°, volume, pressure)

• pulmonary and/or bronchial arteries

• anterograde and/or retrograde flush

• storage conditions (T°, oxygen, inflation)

Techniques (2)

(Novick RJ et al. Ann Thorac Surg 1996;62:302-314)(Kelly RF. J Lab Clin Med 2000;136:427-440)


Flushing Conditions

• high volume (60 ml/kg) - high rate (4 min)

• low PA pressure (10 – 15 mm Hg)

• low temperature (4°C - 8°C)

• ventilation (VT 10 ml/kg; PEEP 5 cm H2O)

• vasodilator (PGE1 - PGI2 - Nitroglycerine)

Techniques (3)


EACTS 16th Annual MeetingMonte CarloBronchial

Arteries• preservation of bronchial tree

• cannula in isolated aortic segment

• 20 - 30 ml/kg

• 60 - 100 mm Hg

Techniques (3)

(Steen S. In Messmer K (ed). Progress in Applied Microcirculation,Basel, Karger, 1996, vol 22, 50-60)

EACTS 16th Annual MeetingMonte CarloRetrograde

Flush• primary (via left atrial appendage)(Sarsam MA et al. J Heart Lung Transplant 1993;12:494-498)

• secondary (via pulmonary veins)(Varela A et al. J Thorac Cardiovasc Surg 1997;114:1119-1120)

• preimplantation (on back-table)(Venuta F et al. J Thorac Cardiovasc Surg 1999;118:107-114)

Techniques (4)

EACTS 16th Annual MeetingMonte CarloStorage

Conditions

• low temperature (4°C)

• (no hyper)inflation (15-20 cm H20)

• oxygen reserve (FiO2 50%)

Techniques (5)



• lung donors




• conclusions


Controversies

• colloid or cristalloid

• intracellular or extracellular

Solutions (1)


Colloid or Crystalloid ?

• colloid (donor blood):+ natural: buffer - substrates - scavengers- preparation prior to organ retrieval

• crystalloid :+ simple method, minimum equipment+ technique applicable to any cristalloid+ wash out of harmful blood constituents+ no interference with other teams- embolization of microvasculature (Mg)

Solutions (2)


Intracellular or Extracellular?

• high K :+ minimize transmembrane ion shift - reflex pulmonary vasoconstriction - endothelial cell damage/permeability

• low K :+ better distribution of flush solution+ uniform cooling of the graft+ lower PVR upon reperfusion+ less hydrostatic edema

Solutions (3)

(Kimblad PO et al. Ann Thorac Surg 1991;52:523-528)


Types

IntracellularIntracellular ExtracellularExtracellular

• modified Euro-Collins (EC) • Perfadex (LPDG)

• University of Wisconsin (UW) • Celsior

• Wallwork

Solutions (4)

EACTS 16th Annual MeetingMonte CarloSurvey

• colloid:

• donor blood (Wallwork - Papworth) (7%)

• crystalloid:

• modified Euro-Collins (m-EC) (78%)

• University of Wisconsin (UW) (15%)


Solutions (5)


Electrolytes (mmol/L) m-EC UW Perfadex Celsior

Na 10 28 138 100 K 115 125 6 15 Cl 15 0 142 41.5Mg 4 5 0.8 13Ca - - 0.3 0.26

pH 7.4 7.6 7.4 7.3mOsm/l 375 327 292 320

Solutions (6)

EACTS 16th Annual MeetingMonte CarloBuffe

r

(mmol/L) m-EC UW Perfadex Celsior

HCO3 10 5 - -

SO4 - 4 0.8 -

PO4 57.5 25 0.8 -

Histidine - - - 30

Solutions (7)


Impermeants

Solutions (8)


mannitol - - - 60lactobionate - 100 - 80

raffinose - 30 - -

glucose 214 - 5 -


Oncotic agents

Solutions (9)

(gm/L) m-EC UW Perfadex Celsior

Dextran-40 - - 50 -Pentastarch - 50 - -


Anti-Oxydants

Solutions (10)


Glutathione - 3 - 3


Energy Precursors

Solutions (11)


Adenosine - 5 - -Glutamate - - - 20


Comparative Studies (1)

Solutions (12)

EC versus UW

(Hardesty R et al. J Thorac Cardiovasc Surg 1993:105:660-6)

• historical comparison, non-randomized study (n = 100)

• EC: n= 30 >< UW n = 70

• no differences (longer ischemic times UW)


Solutions (13)


UW versus Celsior

(D’Armini AM et al. J Heart Lung Transplant 2001:20:183)

• randomized study (n = 20)

• UW: n= 10 >< Celsior: n = 10

• A-aDO2 up to 24 hours better (p<0.05) in UW

• no other differences


Solutions (14)

EC versus Perfadex


(Müller C et al. Transplantation 1999;68:1139-43)(Strüber M et al. Eur J Cardiothorac Surg 2001;19:190-194)

(Fischer S et al. J Thorac Cardiovasc Surg 2001;121:594-596)

• 3 historical comparative, non-randomized studies

• EC: ~ n= 50 >< Perfadex: ~ n = 50

• better (p < 0.05) early graft function in Perfadex group

• better (NS) early survival in Perfadex group


Solutions (15)

EC versus Perfadex (1)


(Rega F et al. Presented at 5th International Congresson Lung Transplantation, Paris, September 19-20, 2002)

166±12182±13212±18

249±22

309±19

174±9

164±11128±10135±10145±10

168±14

234±20

0

100

200

300

400

Donor Arrival ICU 12 h 24 h 36 h 48 h Time

mm HgEC (n = 49)

LPDG (n = 50)A-aDO2

p = 0.59

p < 0.001


Solutions (16)

5257,1

85,8

74,4

5041,03

0

10

20

30

40

50

60

70

80

90

100

30 d 6 months 1 year

Time

%

LPDG (n = 50)

EC (n = 49)




Freedom from

Acute Rejectionp = 0.2

p = 0.66p = 0.17


Solutions (17)




Early Survival

96,0 95,592,3

81,383,389,6

0

20

40

60

80

100

30 days 6 months 1 year

%

LPDG (n = 50)

EC (n = 49)

p = 0.92 p = 0.59 * p < 0.01


Solutions (18)

EC versus UW versus Celsior versus Papworth


(Thabut G et al. Am J Respir Crit Care Med 2001;164:1204-1208)

• French multicenter, non-randomized study (n = 170)

• EC: n = 61 >< UW: n = 24 >< Celsior: n = 21 >< Papworth: n = 64

• lower incidence of reperfusion edema in extracellular solutions

• no difference in 1-month mortality



• lung donors




• conclusions


Reperfusion

Controlled Conditions

• controlled reperfusion(Bhabra MS et al. Ann Thorac Surg 1998;65:187-192)

low PA pressure during first 10 min

- slowly releasing PA clamp- reperfusion on CBP

• controlled ventilation(de Perrot M et al. J Thorac Cardiovasc Surg 2002 in press)


Conclusions

Best Preservation – Worst Graft

• IR-injury: multifactorial (donor - recipient)

• new techniques (retrograde flush)

• new extracellular solutions (Perfadex - Celsior)

• decreased incidence in reperfusion edema

• more extended donors with less optimal grafts

• better early outcome (less acute rejection)

• better late outcome? (less BOS)


Acknowledgments

• Dr F. Rega, research fellow

• Leuven Lung Transplant Group

(www.longtransplantatie.be)

EACTS 16th Annual MeetingMonte CarloThank you for your attention

www.dirkvanraemdonck.be

advances in lung transplantation “the best preservation solution for the worst graft”

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